The project is to investigate radiation-induced .genomic instability, defined as a phenomenon whereby radiation related genetic damage manifests itself one or more cell generations following the generation in which damage was inflicted. Although the mechanism is not fully understood, it is believed that both DNAtargeted and non-DNA targeted effects of. radiation contribute. Genomic instability increases the risk of cancer, potentially affects tissue aging, and presents a risk to unexposed future generations. In contrast to conventional radiation effects, genomic instability has a complex and possibly nonlinear dose-response relationship, and is thus particularly relevant to low dose and low dose-rate environmental exposures. This project will identify genetic pathways that protect against radiation-induced genomic instability in vivo. It will use a novel whole-animal model, the Japanese Medaka fish (Oryzias latipes), that is similar to higher vertebrates in terms of organ systems and pattern of development and has homologs of most mammalian DNA damage surveillance and repair genes. Of relevance to work proposed here, medaka is a genetically tractable model with established technologies for transgenesis and gene silencing, where large numbers of individuals can be phenotypically screened, and with a short generation time facilitating multigenerational studies. Genomic instability will be measured in vivo based on a locus-specific test based on an unstable, engineered transgene. Individual aims are: (1) to characterize the tissue-specific dose response to low dose ionizing radiation using somatic recombination as an indicator of genomic instability, (2) to investigate how the tissue-specific response to low dose ionizing radiation is modified as a function of genetic and phenotypic background, and (3) to identify conditions under which genomic instability is transmitted to future generations and to identify factors that modify transgenerational risk. The significance of this study is to provide an opportunity to identify germline pathways of radiation response on an organism-wide scale that is not feasible in higher vertebrate models. Because of the high degree of functional gene conservation among vertebrates, mechanisms identified in the O. latipes model can readily be evaluated in mammalian species and the results then extrapolated to human. ,